Mitochondrial dysfunction has been associated with many neurodegenerative disorders including Alzheimer's Disease (AD) and Parkinson's Disease (PD). Mitochondrial dynamics and axonal trafficking are required for synaptogenesis and synaptic strengthening. It is proposed that mitochondria may act as local sources of ATP or as sites of presynaptic calcium buffering and re- release during synaptic plasticity and that these processes could be altered in neurodegenerative disease. However, the mechanisms of how mitochondria meet the high energy demands and calcium buffering requirements during synaptic plasticity are incompletely studied. Mitochondrial permeability transition pore (mPTP) activity is critical to determining inner membrane permeability and cell death under pathological conditions. However, very little is known regarding physiological function of the calcium-regulated inner membrane permeability transition pore during synaptic transmission. We reported previously that an unknown channel governs mitochondrial ion channel activity that is necessary for short term synaptic plasticity in response to high frequency synaptic activity. This mitochondrial channel activity is inhibited by the small molecule Bcl-xL inhibitor ABT- 737 and ABT-737 also attenuates synaptic function. Recently we found that Bcl-xL localizes to mitochondrial inner membrane and interacts with the F1FO ATP synthase; the interaction is required to prevent proton leak through an inner membrane channel and to regulate ATP production. Our preliminary data suggest that the non-selective ion channel affected by Bcl-xL is the mitochondrial permeability transition pore (mPTP) and that it is located within the c-subunit of the FO of the ATP synthase. We therefore hypothesize that during synaptic transmission, Bcl-xL translocates to the mitochondrial inner membrane and improves mPTP gating to enhance the degree of mitochondrial calcium efflux following intense synaptic events. In the absence of Bcl-xL the pore will not open properly, and defects in calcium efflux from mitochondria will occur. These defects may contribute to a loss of synaptic plasticity.